Abstract 18803: Myeloid Derived S100/calgranulins Promotes Visceral Obesity, Diabetes and Calcific Aortic Valve Disease in Transgenic Mice

Abstract

Circulating serum levels of human S100/calgranulins have been associated with diabetes, coronary artery disease and increased cardiovascular mortality in clinical studies. To test whether S100/calgranulins are biomarker of inflammation or directly mediate disease, we generated a novel humanized mouse with transgenic expression of human S100/calgranulin by expression of a bacterial artificial chromosome of the human S100/calgranulin gene cluster containing genes and regulatory elements for S100A8/9 and S100A12 (60kb) in C57BL6 mice. F3 animals of the hBAC-S100 mice their wild type (WT) control littermate mice on regular rodent chow diet or on high fat diet (HFD) were studied. Results: hBac-100 mice express human S100A12 in circulating myeloid cells and S100A12 was present in the serum of hBAC-S100 mice (25 ng/ml serum), but was not detected in WT mice. Moreover, serum IL-6 was elevated in hBAC-S100 mice at age 3 and 12 month. hBAC-S100 mice developed increased visceral adiposity after 12 months on regular chow diet (25% vs 12% body fat upon DEXA scanning, p<0.05), or after 3 months on HFD. White adipose tissue (WAT) of lean hBAC-S100 age 4 weeks showed increased expression of T- and B cell marker and no macrophage marker compared to WT, followed by increase in gene expression for F4/80, CD68 and MCP-1 in obese hBAC-S100. Importantly, impaired oral glucose tolerance and hyperinsulinemia preceded the onset of adiposity in hBAC-S100 mice. Metabolic cage studies indicate reduced oxygen consumption and CO2 production as one mechanism leading to adiposity. This phenotype was attenuated in hBAC-S100 mice lacking RAGE. Moreover, 12-months old hBAC-S100 mice develop calcification of the aortic valve leafleat with presence of osteoblast-like cells in the ascending aortic media upon staining with Alizarin Red S. In vivo ECHO showed abnormal mitral valve doppler flow with reduced ratio of early (E) to atrial (A) filling (E/A ratio 0.85 and 1.22, p=0.03) indicative of diastolic dysfunction. Conclusion: Circulating myeloid derived human S100/calgranulin is sufficient to induce a sustained inflammatory state and is associated with the development of hyperinsulinemia, impaired glucose tolerance, adiposity and aortic valve calcification.